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NM_020975.6(RET):c.2288A>T (p.Asn763Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 20, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000564342.6

Allele description [Variation Report for NM_020975.6(RET):c.2288A>T (p.Asn763Ile)]

NM_020975.6(RET):c.2288A>T (p.Asn763Ile)

Gene:
RET:ret proto-oncogene [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q11.21
Genomic location:
Preferred name:
NM_020975.6(RET):c.2288A>T (p.Asn763Ile)
HGVS:
  • NC_000010.11:g.43118376A>T
  • NG_007489.1:g.46308A>T
  • NM_000323.2:c.2288A>T
  • NM_001355216.2:c.1526A>T
  • NM_001406743.1:c.2288A>T
  • NM_001406744.1:c.2288A>T
  • NM_001406759.1:c.2288A>T
  • NM_001406760.1:c.2288A>T
  • NM_001406761.1:c.2159A>T
  • NM_001406762.1:c.2159A>T
  • NM_001406763.1:c.2153A>T
  • NM_001406764.1:c.2159A>T
  • NM_001406765.1:c.2153A>T
  • NM_001406766.1:c.2000A>T
  • NM_001406767.1:c.2000A>T
  • NM_001406768.1:c.2024A>T
  • NM_001406769.1:c.1892A>T
  • NM_001406770.1:c.2000A>T
  • NM_001406771.1:c.1850A>T
  • NM_001406772.1:c.1892A>T
  • NM_001406773.1:c.1850A>T
  • NM_001406774.1:c.1763A>T
  • NM_001406775.1:c.1562A>T
  • NM_001406776.1:c.1562A>T
  • NM_001406777.1:c.1562A>T
  • NM_001406778.1:c.1562A>T
  • NM_001406779.1:c.1391A>T
  • NM_001406780.1:c.1391A>T
  • NM_001406781.1:c.1391A>T
  • NM_001406782.1:c.1391A>T
  • NM_001406783.1:c.1262A>T
  • NM_001406784.1:c.1298A>T
  • NM_001406785.1:c.1271A>T
  • NM_001406786.1:c.1262A>T
  • NM_001406787.1:c.1256A>T
  • NM_001406788.1:c.1103A>T
  • NM_001406789.1:c.1103A>T
  • NM_001406790.1:c.1103A>T
  • NM_001406791.1:c.983A>T
  • NM_001406792.1:c.839A>T
  • NM_001406793.1:c.839A>T
  • NM_001406794.1:c.839A>T
  • NM_020629.2:c.2288A>T
  • NM_020630.7:c.2288A>T
  • NM_020975.6:c.2288A>TMANE SELECT
  • NP_000314.1:p.Asn763Ile
  • NP_001342145.1:p.Asn509Ile
  • NP_001342145.1:p.Asn509Ile
  • NP_001393672.1:p.Asn763Ile
  • NP_001393673.1:p.Asn763Ile
  • NP_001393688.1:p.Asn763Ile
  • NP_001393689.1:p.Asn763Ile
  • NP_001393690.1:p.Asn720Ile
  • NP_001393691.1:p.Asn720Ile
  • NP_001393692.1:p.Asn718Ile
  • NP_001393693.1:p.Asn720Ile
  • NP_001393694.1:p.Asn718Ile
  • NP_001393695.1:p.Asn667Ile
  • NP_001393696.1:p.Asn667Ile
  • NP_001393697.1:p.Asn675Ile
  • NP_001393698.1:p.Asn631Ile
  • NP_001393699.1:p.Asn667Ile
  • NP_001393700.1:p.Asn617Ile
  • NP_001393701.1:p.Asn631Ile
  • NP_001393702.1:p.Asn617Ile
  • NP_001393703.1:p.Asn588Ile
  • NP_001393704.1:p.Asn521Ile
  • NP_001393705.1:p.Asn521Ile
  • NP_001393706.1:p.Asn521Ile
  • NP_001393707.1:p.Asn521Ile
  • NP_001393708.1:p.Asn464Ile
  • NP_001393709.1:p.Asn464Ile
  • NP_001393710.1:p.Asn464Ile
  • NP_001393711.1:p.Asn464Ile
  • NP_001393712.1:p.Asn421Ile
  • NP_001393713.1:p.Asn433Ile
  • NP_001393714.1:p.Asn424Ile
  • NP_001393715.1:p.Asn421Ile
  • NP_001393716.1:p.Asn419Ile
  • NP_001393717.1:p.Asn368Ile
  • NP_001393718.1:p.Asn368Ile
  • NP_001393719.1:p.Asn368Ile
  • NP_001393720.1:p.Asn328Ile
  • NP_001393721.1:p.Asn280Ile
  • NP_001393722.1:p.Asn280Ile
  • NP_001393723.1:p.Asn280Ile
  • NP_065680.1:p.Asn763Ile
  • NP_065681.1:p.Asn763Ile
  • NP_065681.1:p.Asn763Ile
  • NP_065681.1:p.Asn763Ile
  • NP_066124.1:p.Asn763Ile
  • NP_066124.1:p.Asn763Ile
  • LRG_518t1:c.2288A>T
  • LRG_518t2:c.2288A>T
  • LRG_518:g.46308A>T
  • LRG_518p1:p.Asn763Ile
  • LRG_518p2:p.Asn763Ile
  • NC_000010.10:g.43613824A>T
  • NM_001355216.1:c.1526A>T
  • NM_020630.4:c.2288A>T
  • NM_020630.6:c.2288A>T
  • NM_020975.4:c.2288A>T
Protein change:
N280I
Links:
dbSNP: rs199882293
NCBI 1000 Genomes Browser:
rs199882293
Molecular consequence:
  • NM_000323.2:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001355216.2:c.1526A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406743.1:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406744.1:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406759.1:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406760.1:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406761.1:c.2159A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406762.1:c.2159A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406763.1:c.2153A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406764.1:c.2159A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406765.1:c.2153A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406766.1:c.2000A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406767.1:c.2000A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406768.1:c.2024A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406769.1:c.1892A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406770.1:c.2000A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406771.1:c.1850A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406772.1:c.1892A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406773.1:c.1850A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406774.1:c.1763A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406775.1:c.1562A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406776.1:c.1562A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406777.1:c.1562A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406778.1:c.1562A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406779.1:c.1391A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406780.1:c.1391A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406781.1:c.1391A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406782.1:c.1391A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406783.1:c.1262A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406784.1:c.1298A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406785.1:c.1271A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406786.1:c.1262A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406787.1:c.1256A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406788.1:c.1103A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406789.1:c.1103A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406790.1:c.1103A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406791.1:c.983A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406792.1:c.839A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406793.1:c.839A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406794.1:c.839A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020629.2:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020630.7:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020975.6:c.2288A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000674852Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Mar 20, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach.

George Priya Doss C, Rajith B, Chakraboty C, Balaji V, Magesh R, Gowthami B, Menon S, Swati M, Trivedi M, Paul J, Vasan R, Das M.

Mol Biosyst. 2014 Mar 4;10(3):421-36. doi: 10.1039/c3mb70427k. Epub 2013 Dec 12.

PubMed [citation]
PMID:
24336963

Details of each submission

From Ambry Genetics, SCV000674852.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The p.N763I variant (also known as c.2288A>T), located in coding exon 13 of the RET gene, results from an A to T substitution at nucleotide position 2288. The asparagine at codon 763 is replaced by isoleucine, an amino acid with dissimilar properties. In one study examining physicochemical properties (changes in size, charge, polarity and hydrophobicity) and protein accessibility, this alteration is predicted to be neutral (George Priya Doss C et al. Mol Biosyst 2014 Mar; 10(3):421-36). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in association with MEN2 based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024